Metformin Exerts Anti-inflammatory and Mucus Barrier Protective Effects by Enriching Akkermansia muciniphila in Mice With Ulcerative Colitis.

Haoran Ke,Pinjing Lv,Ye Chen,Fang Li,Zitong Li,Wenlin Deng,Siqi Wang

doi:10.3389/fphar.2021.726707

Abstract

The present study aimed to determine if metformin exerts anti-inflammatory and mucus-protective effects via the gut microbiota. Metformin has extensive benefits including anti-inflammatory effects. Previous studies showed that metformin changed the gut microbiota composition and increases the number of goblet cells. Intestinal dysbiosis and goblet cell depletion are important features of ulcerative colitis (UC). The underlying mechanism and whether metformin can improve the mucus barrier in UC remain unclear. Metformin (400 mg/kg/day) was administered to mice with dextran sulfate sodium (DSS)-induced UC for 2 wk to investigate the effects of metformin on the intestinal mucus barrier. The gut microbiota was depleted, using antibiotics, to explore its role in the mucus-protecting effects of metformin. Akkermansia muciniphila (A. muciniphila), which was enriched in metformin-treated mice, was administered to mice to investigate the effects of the bacteria on UC and the mucus barrier. Metformin attenuated DSS-induced UC in mice, as evidenced by the alleviation of diarrhea, hematochezia, and the decrease in body weight. The expression of mucin2, a prominent mucus barrier protein, was increased in the metformin-treated group compared to the DSS-treated group. Furthermore, fecal 16S rRNA analysis showed that metformin treatment changed the gut microbiota composition by increasing the relative abundance of Lactobacillus and Akkermansia species while decreasing Erysipelatoclostridium at the genus level. Antibiotic treatment partly abolished the anti-inflammatory and mucus-protecting effects of metformin. Administration of A. muciniphila alleviated the colonic inflammation and mucus barrier disruption. Metformin alleviated DSS-induced UC in mice and protected against cell damage via affecting the gut microbiota, thereby providing a new mechanism for the therapeutic effect of metformin in patients with UC. This study also provides evidence that A. muciniphila as a probiotic has potential benefits for UC.

Highlights

Ulcerative colitis (UC), characterized by chronic and relapsing inflammation in the colon, is becoming a global disease (M’Koma, 2013)
The present study shows that metformin reduced colonic inflammation and protected against mucus barrier disruption along with an alteration of the gut microbiota during UC
Depletion of the gut microbiota partly abolished the anti-inflammatory and mucus-protective effects of metformin, indicating that metformin exerts its effects via the gut microbiota

Summary

Introduction

Ulcerative colitis (UC), characterized by chronic and relapsing inflammation in the colon, is becoming a global disease (M’Koma, 2013). It is thought to involve genetic factors, abnormal immune responses, environmental factors, intestinal barrier dysfunction, and dysbiosis (Zhang and Li, 2014; Testa et al, 2017; Ungaro et al, 2017). Mucus barrier dysfunction plays a significant role in the pathogenesis of UC. The mucus barrier, organized by the Mucin (Muc2) mucin, is a gel that covers the intestinal epithelium (Johansson and Hansson, 2011; Kühn and Klar, 2015). Several studies have shown that the thickness of the mucus is decreased in wild-type mice with DSS-induced UC, while Muc2-deficient mice developed spontaneous UC and were more susceptible to DSS-induced colitis (Van der Sluis et al, 2006; Heazlewood et al, 2008; Petersson et al, 2010). The mucus barrier is impaired in patients with UC (Shen et al, 2018) (Van der Post et al, 2019)

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